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Abstract
Post-stroke cognitive impairment (PSCI) is a major source of disability, affecting up to two thirds of stroke survivors with no available therapeutic options. The condition remains understudied in preclinical models due to its delayed presentation. Although hypertension is a leading risk factor for dementia, how ischemic stroke contributes to this neurodegenerative condition is unknown. In this work, we used a model of hypertension to study the development of PSCI and its mechanisms, in addition to investigating the delayed activation of Angiotensin II type 2 receptor (AT2R) as a potential therapeutic mechanism.
In the first set of investigations, spontaneously hypertensive rats (SHR) were compared to normotensive rats and were subjected to 1-hour middle cerebral artery occlusion (MCAO) or sham surgery. Several cognitive tests were used to assess cognition. Brain magnetic resonance images (MRI) were obtained 12-weeks post-stroke and tissue was collected for immunohistochemistry and protein quantification. Stroked animals developed memory impairment at 4-weeks post-stroke despite recovery from motor deficits. SHRs displayed grey matter atrophy and showed increased markers of inflammatory cell death and DNA damage. This indicates that preexisting hypertension exacerbates neurodegeneration after stroke beyond its acute effects on neurovascular injury.
In the second set, we ran a randomized, controlled, blinded preclinical trial to determine the therapeutic potential of delayed administration of compound 21 (C21) on these animals. SHRs were subjected to 60-min MCAO or sham surgery. They received C21 or water (orally) for 8 weeks, starting 3 days post-MCAO. Several tests were utilized to assess sensorimotor and cognitive function. Markers of inflammation, cell-death and DNA damage were quantified in the brain lysates. Stroked animals suffered significant sensorimotor deficits that improved overtime and cognitive deficits compared to sham animals. However, delayed treatment with C21 was not effective in improving the rate of sensorimotor recovery or preventing cognitive deficits.
In conclusion, this dissertation provides a better understanding to the role hypertension plays in the development of post stroke cognitive impairment. It proves that there is still a long way to go to produce better treatments to reduce post-stroke disability, beyond treatments that target reducing the initial ischemic insult.
In the first set of investigations, spontaneously hypertensive rats (SHR) were compared to normotensive rats and were subjected to 1-hour middle cerebral artery occlusion (MCAO) or sham surgery. Several cognitive tests were used to assess cognition. Brain magnetic resonance images (MRI) were obtained 12-weeks post-stroke and tissue was collected for immunohistochemistry and protein quantification. Stroked animals developed memory impairment at 4-weeks post-stroke despite recovery from motor deficits. SHRs displayed grey matter atrophy and showed increased markers of inflammatory cell death and DNA damage. This indicates that preexisting hypertension exacerbates neurodegeneration after stroke beyond its acute effects on neurovascular injury.
In the second set, we ran a randomized, controlled, blinded preclinical trial to determine the therapeutic potential of delayed administration of compound 21 (C21) on these animals. SHRs were subjected to 60-min MCAO or sham surgery. They received C21 or water (orally) for 8 weeks, starting 3 days post-MCAO. Several tests were utilized to assess sensorimotor and cognitive function. Markers of inflammation, cell-death and DNA damage were quantified in the brain lysates. Stroked animals suffered significant sensorimotor deficits that improved overtime and cognitive deficits compared to sham animals. However, delayed treatment with C21 was not effective in improving the rate of sensorimotor recovery or preventing cognitive deficits.
In conclusion, this dissertation provides a better understanding to the role hypertension plays in the development of post stroke cognitive impairment. It proves that there is still a long way to go to produce better treatments to reduce post-stroke disability, beyond treatments that target reducing the initial ischemic insult.